Squamous cell carcinomas (SCCs) of the gastrointestinal tract result in significant morbidity and mortality; SCCs are epithelial tumors comprised of abnormal keratinocytes. Most SCCs of the gastrointestinal tract arise in the esophagus and oral cavity. Knowledge of the molecular mechanisms that regulate keratinocyte proliferation and differentiation will provide insight into the pathophysiology of SCCs. In SCC of the esophagus and oral cavity, up- regulation of the EGF receptor, a molecule associated with keratinocyte proliferation has been demonstrated. Therefore, study of signaling pathways in keratinocytes that regulate EGF receptor signaling may provide useful insights into regulation of keratinocyte proliferation. The Src family tyrosine kinase Fyn has a role in keratinocyte differentiation. In murine keratinocytes, increased Fyn kinase activity decreases EGF receptor phosphorylation. In addition, increased Fyn activity induces keratinocytes to withdraw from the cell cycle and differentiate. To further delineate Fyn signaling pathways in keratinocytes, we have isolated a novel Fyn substrate termed Srcasm: Src activating and signaling molecule. Further study of Srcasm will provide into how Fyn signaling pathways promote keratinocyte differentiation and inhibit keratinocyte proliferation.